DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
Claims 1-17 are pending in the instant application and subject to examination herein.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 09/30/2024, 07/10/2025, and 12/23/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 12 and 14-15 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 12 and 14-15 are drawn to methods to treat or ameliorate a disease in a subject in need thereof, comprising administering a compound of the instant invention, or a form thereof, whether a compound of instant Formula (I), as in claim 12, or a specific compound as listed in each of claims 10-11, “to inhibit dihyrdroorotate dehydrogenase”. These claims are indefinite because they do not identify any specific patient population, as the claims are not drawn to any particular disease(s) and/or disorder(s), and a person of ordinary skill in the art would not be able to determine the metes and bounds of the claim by extrapolating from the claim limitation that the mechanism of the method is to inhibit the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH).
The instant Specification states that “inhibitors of DHODH have been used to treat autoimmune diseases and are in clinical trials for cancer and viral infections”, and goes on to list specific examples of rheumatoid arthritis, acute myeloid leukemia, glioma, and RNA virus infections, including COVID-19 (pages 1-2, bridging paragraph). However, the instant Specification does not further elaborate which autoimmune diseases, cancers, and viral infections are appropriate for treatment that comprises administration of an inhibitor of DHODH, or whether such treatment extends to all autoimmune diseases, cancers, and viral infections, and/or whether other diseases that are not autoimmune diseases, cancer or viral infections are also relevant to a method of treatment that functions by inhibition of DHODH.
A review of the field of art shows that inhibition of DHODH does extend beyond the diseases/disorders listed in the instant Specification, as evidenced by Munier-Lehmann (Munier-Lehmann, et al., Journal of Medicinal Chemistry, v56, pp3148-3167; 2013), who teaches a review on inhibitors of DHODH and their uses, and teaches that DHODH inhibitors are used in medicine to treat autoimmune diseases such as rheumatoid arthritis or multiple sclerosis (leflunomide and teriflunomide) and have been investigated in treatments of cancer, virus, and parasite infections (i.e., malaria) as well as in crop science. The last of these disease/disorder examples, crop science, would not be relevant to the instant claims, as the “subject in need thereof” is limited by the instant Specification to an “an animal or any living organism having sensation and the power of voluntary movement, and which requires oxygen and organic food” (page 190). However, infectious diseases of parasites (other than viruses) are not listed by Applicant in the instant Specification as among the diseases that DHODH inhibitors are known to treat. While Munier-Lehmann teaches the treatment of parasitic infections by Trypanosoma cruzi, which causes Chagas disease, and Plasmodium falciparum, which causes malaria (3150-3151, bridging paragraph), Munier-Lehmann does not provide a full scope of parasitic diseases treatable by inhibition of DHODH. A more thorough discussion of DHODH inhibitors in anti-infective treatments is provided by Boschi (Boschi, et al.; European Journal of Medicinal Chemistry, v183, article 111681, pp1-21; 2019). Boschi provides an review of various pathogenic organisms that infect animals (including humans), and their diseases and inhibition by DHODH inhibitors, including leishmania (page 3), trypanosomiasis (page 4), bacterial infections by Helicobacter pylori and Pseudomonas aeruginosa (pages 8-9), fungal infection by Aspergillis fumigatus (pages 10-11), protozoan infections by Toxoplasmosis gondii and plasmodium species like Plasmodium falciparum (pages 11-15), trematode worms such as Schistosoma mansoni that cause schistosomiasis, (page 16) and specifically veterinary pathogens like Babesia bovis, Babesia caballi and Theileria equi, that plague cows and horses, respectively (pages 15-16). Boschi concludes with a discussion on how future DHODH inhibitors can be screened and developed for the pathogens discussed therein, and other pathogens previously unaddressed by DHODH inhibition (pages 16-17). The prospect of new targets for DHODH inhibition of parasitic diseases and disorders is answered by the teaching of Sato (Sato, et al.; Genes, v11, article 1468, pp1-18; 2021) who, coming a year after Boschi, shows that DHODH inhibition can be useful to treat parasitic infections of chickens by the protozoan Eimeria tenella (Abstract). Thus, the field of art of treating diseases and disorders by DHODH inhibition, as exemplified by the teachings of Munier-Lehmann, Boschi and Sato, tells an unfinished story, showing that the reach of parasitic infectious diseases treatable by DHODH inhibitors is broad and as yet undetermined, while the scope of autoimmune diseases, cancers and viral infections is nonspecific outside of a few known examples. Claims 12 and 14-15 are indefinite because a person of ordinary skill in the art would not be able to discern what patient population(s) are appropriate for a method of treating an unidentified disease or a disorder in a subject in need thereof by administering a compound of the instant invention, knowing only that the compound is a DHODH inhibitor.
For the purpose of compact prosecution, claims 12 and 14-15 will be examined herein with the interpretation of “a disease or disorder” representing a Markush group of disease(s)/disorder(s) that includes rheumatoid arthritis, acute myeloid leukemia, glioma, and RNA virus infections, including COVID-19.
Claims 14-15 are further indefinite because these claims, which depend from claims 10-11, respectively, invoke “a compound of Formula (I), or a form thereof” of the each of claims 10-11, respectively, while neither of claims 10-11 provide, disclose or claim any genus of compounds described by a structural Formula, including Formula (I). Claims 10-11 each provide a list of specific compounds without reference to any structural Formula. Claim 1 provides the structure of instant Formula (I); however neither of claims 10-11 depend from claim 1. Thus, there is a lack of antecedent basis in each of claims 14-15, for invoking “a compound of Formula (I), or a form thereof”.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim 1, 3-9 and 12-13 are anticipated by Moon.
Claims 1, 3-9 and 12-13 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Moon (U.S. PG Pub 2005/0272759 A1).
Claim 1 is drawn to a genus of tetrahydrocarboline compounds, designated as Formula (I), bearing pendant heteroaryl and/or aryl rings and further limitations as shown in the table below. Moon discloses a series of carboline derivatives useful in the inhibition of angiogenesis by the inhibition of the expression of Vascular Endothelial Growth Factor (VEGF) (Title/Abstract), including multiple compounds that anticipate the instant genus of Formula (I), including Moon’s compound 251 shown in the table below (paragraph [0090]/page 22, and paragraphs [0200]-[0201]):
Claim Number(s) of Instant Application
Instant Application
Moon (US 2005/0272759 A1)
1
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200
276
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wherein:
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164
242
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Moon’s compound 25 differs from the scope of instant Formula (I) in that all of R5, R6 and R7 are hydrogen, whereas claim 1 requires that at least one of these positions must be a substituent other than hydrogen, for example deuterium. However, a person of ordinary skill in the art would at once recognize that the presence of deuterium atoms is inherent even in compounds not enriched with deuterium, as evidenced by Olgun (Olgun, et al.; Annals of the New York Academy of Sciences, v1100, pp.400-403; 2007). Olgun discloses that the natural abundance of deuterium is 1 per ~6600 hydrogen atoms. Since every preparation of the compounds disclosed by Moon or in the instant application will have some measure of molecules bearing deuterium atoms in place of hydrogen atoms, including at positions R5, R6 and R7, the administration of a deuterated version of the compound disclosed by Moon is inherent. Exemplary naturally abundant deuterated isotopologues of Moon’s compound 25, with deuterium at positions R5, R6 or R7, are shown below:
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304
374
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262
406
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264
386
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(naturally abundant deuterated isotopologues of Moon’s compound 25).
Thus, claim 1 is anticipated by the disclosure of Moon.
Claim 3 further limits claim 1 to wherein R2 is selected from a Markush group that includes a halogen atom, and is met by the rejection above.
Claim 4 further limits claim 1 to wherein R2 is selected from a Markush group that includes a bromine atom, and is met by the rejection above.
Claims 5 and 6 further limit claim 1, each to a narrower genus of compounds wherein R5 and R7 are selected from a Markush group that includes hydrogen, and each is met by the exemplary naturally abundant isotopologue shown above wherein position R6 is deuterium.
Claim 7 further limits claim 1 to wherein R6 is selected from a Markush group that includes hydrogen, and is met by two of the three exemplary naturally abundant isotopologues shown above, wherein either R5 or R7 is deuterium.
Claims 8 and 9 further limit claim 1, each to a narrower genus of compounds wherein R9 is selected from a Markush group that includes hydrogen, and each is met by any of the exemplary naturally abundant isotopologues shown above.
Claim 12 is drawn to a method of use of a compound of Formula (I), or a form thereof, to treat or ameliorate a disease or disorder in a subject in need thereof comprising administering to the subject an effective amount of a compound of Formula (I), or a form thereof, to inhibit dihydroorotate dehydrogenase. As discussed in the 112(b) rejection above, the term “a disease or disorder” in claim 12 is interpreted as being a disease or disorder selected from the Markush group that includes rheumatoid arthritis, acute myeloid leukemia, glioma, and RNA virus infections, including COVID-19. Moon discloses methods for treating diseases, including rheumatoid arthritis, comprising a therapeutically effective amount of at least one compound of the invention disclosed therein, which would include the exemplary naturally abundant isotopologues presented in the rejection above (paragraph [0015]). The treatment disclosed by Moon is based on the inhibition of the expression of VEGF, as discussed above, and Moon further discloses that the inactivation of VEGF signaling has been proven to be highly effective in treatment of a broad range of tumors, including gliomas (paragraph [0008]).
Claim 13 further limits claim 1 to a pharmaceutical composition comprising a compound of Formula (I), or a form thereof, and a pharmaceutically acceptable excipient to treat or ameliorate a disease or disorder by inhibiting dihydroorotate dehydrogenase. The intended use of the composition is not limiting on the structure of the composition. Moon discloses pharmaceutical compositions that comprise the compounds disclosed therein, “may be formulated with pharmaceutically acceptable excipients such as carriers, solvents, stabilizers, adjuvants, diluents, etc., depending upon the particular mode of administration and dosage form” (paragraph [0131]).
Thus, claims 3-9 and 12-13 are anticipated by the disclosure of Moon.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3-9 and 12-13 are unpatentable over Moon in view of Brown.
Claims 1, 3-9 and 12-13 are rejected under 35 U.S.C. 103 as being unpatentable over Moon (US PG Pub 2005/0272759 A1) in view of Brown (Brown; Bioisosteres in Medicinal Chemistry, Wiley-VCH, 2012).
The limitations of claims 1, 3-9 and 12-13 and the disclosure of Moon are discussed above.
As discussed above, Moon’s compound 25 differs from the scope of instant Formula (I) in that all of R5, R6 and R7 are hydrogen, whereas claim 1 requires that at least one of these positions on the pyrimidyl ring must be a substituent other than hydrogen, for example fluorine. However, a person of ordinary skill in the art would have a reasonable expectation of success in selecting a pyrimidyl ring having a pendant fluorine atom in place of the unsubstituted pyrimidyl ring, because fluorine and hydrogen atoms are known as bioisosterically equivalent substituents. For example, see Brown.
Brown teaches that “bioisosteric replacement of substituents, ring atoms, linkers, and other groups aims to generate chemical substitutes with related biological properties.” Brown also teaches that hydrogen and fluorine substituents both fall with a common grouping of “Monovalent atoms or groups” within “classical bioisoteric examples” (pp6-7, Table 1.3), and within this grouping, hydrogen and fluorine in particular are considered to be substantially equivalent (same row, Table 1.3). Brown further teaches that one of the most common monovalent isosteric replacements is the substitution of hydrogen with fluorine. These atoms have similar van der Waals radii but different electronic effects, fluorine being the most electronegative element in the periodic table. Due to the high strength of the C-F bond, fluorine is often introduced to achieve metabolic stability. Moreover, due to its high electronegativity, fluorine can be introduced to reduce basicity of proximal amines or increase acidity of proximal acids and also to introduce a conformational bias in molecules. Exemplary bioisosteric analogues of Moon’s compound 25, with fluorine at positions R5, R6 or R7, are shown below:
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262
360
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(fluoridated bioisosteric analogues of Moon’s compound 25).
Applicant’s invention is unpatentable over the disclosure over the disclosure of Moon in view of the teaching of Brown, because a person of ordinary skill in the art would have had, at the time of filing, a reasonable expectation of success in making and using a fluoridated derivative of Moon’s compound 25, wherein one or more hydrogen atoms on positions R5, R6 and/or R7 of the pyrimidyl ring are replaced with fluorine, because hydrogen and fluorine substituents are bioisosterically equivalent and such replacements of hydrogen for fluorine can be expected to result in analogous compounds with related biological properties.
Thus, the invention was prima facie obvious at the time of filing.
Claims 3-9 further limit claim 1, each to a narrower genus of compounds, and each is met by the bioisosteric fluoridation of Moon’s compound 25 discussed above.
The limitations of claims 12-13 are discussed in the rejection above and are met by disclosure of Moon in view of the bioisosteric fluoridation of Moon’s compound 25 discussed above.
Applicant’s invention is unpatentable over the disclosure over the disclosure of Moon in view of the teaching of Brown, because a person of ordinary skill in the art would have had, at the time of filing, a reasonable expectation of success in making a fluoridated derivative of Moon’s compound 25, wherein one or more hydrogen atoms on positions R5, R6 and/or R7 of the pyrimidyl ring are replaced with fluorine, and further preparing a pharmaceutical composition comprising such a fluoridated bioisosteric analogue and/or using such a fluoridated bioisosteric analogue in a method for treatment of rheumatoid arthritis and/or glioma, because hydrogen and fluorine substituents are bioisosterically equivalent and such replacements of hydrogen for fluorine can be expected to result in analogous compounds with related biological properties, and Moon provides for the preparation and use of pharmaceutical compositions and methods for the treatment of rheumatoid arthritis and glioma.
Thus, the invention was prima facie obvious at the time of filing.
Claims Free of the Prior Art
Claims 10-11 and 16-17 are allowed. Prior art does not teach or reasonably suggest, alone or in combination, any of the specific compounds of claim 10, or a form thereof consisting of a salt, hydrate, solvate, racemate, enantiomer, diastereomer, stereoisomer, and tautomer, or a pharmaceutical composition comprising such a compound or form thereof along with a pharmaceutically acceptable excipient. Prior art does not teach or reasonably suggest, alone or in combination, any of the specific compound salts of claim 11, or a form thereof consisting of a hydrate, solvate, racemate, enantiomer, diastereomer, stereoisomer, and tautomer, or a pharmaceutical composition comprising such a compound salt or form thereof along with a pharmaceutically acceptable excipient.
Claim 2 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to W. JUSTIN YOUNGBLOOD whose telephone number is (703)756-5979. The examiner can normally be reached on Monday-Thursday from 8am to 5pm. The examiner can also be reached on alternate Fridays.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey S. Lundgren, can be reached at telephone number (571) 272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/W.J.Y./Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
1 6-Bromo-2,3,4,9-tetrahydro-1-[4-(1-methylethyl)phenyl]-2-(2-pyrimidinyl)-1H-pyrido[3,4-b]indole
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